PROJECT SUMMARY Ankylosing spondylitis (AS) is a relatively common form of inflammatory arthritis of the spine that may cause severe disability and reduced quality of life. In addition to the spine, AS may cause arthritis of other joints, most commonly the hip and knee, causing the need for joint replacement surgery. Additionally, local and system- wide inflammation may lead to reduced bone density and fractures even in early disease. While the primary goal of AS treatment is to control spinal inflammation, an important secondary goal is to improve overall quality of life, but little data exist to date about whether available treatments have effects on AS complications that may also affect quality of life. Knowledge about how AS treatments impact disease complications would inform shared decision-making between AS patients and their healthcare providers. The goal of this proposal is to estimate the effects of tumor necrosis factor inhibitors (TNFi) on AS complications, including end-stage arthritis of the hip and knee (joint replacements) and fractures. The proposed work will translate basic immunology knowledge about the effects of inflammation on bone into population science. This work will be among the first to assess the effects of TNFi on joint replacement surgeries and fractures, using data from 3 large databases derived from electronic medical records and billing records, and importantly will include data specific to the US population. We will use both nested case-control studies and compare trends in these outcomes between patients with AS in the pre-TNFi and TNFi eras versus the general population to also understand overall improvements in general medical care. On completion of the proposed studies, we will have evidence for the effects of TNFi on AS manifestations beyond the effects on spinal inflammation. This knowledge will inform shared decision-making between AS patients and their healthcare providers in selecting therapies, and may provide rationale for earlier treatment with TNFi for insurers and other payors.